Epoxycarboxamide compound, azide compound, and amino alcohol compound, and process for preparing alpha-keto amide compound using them

ABSTRACT

The present invention is to provide manufacturing intermediates which can be led to useful α-ketoamide compounds having protease-inhibiting activity extremely economically and stereoselectively, and to provide epoxycarboxamide compounds, azide compounds and amino alcohol compounds represented by the following formulae:  
                 
         wherein R 1  and R 2  each represents alkyl group, alkenyl group, aromatic hydrocarbon group or heterocyclic group; R 3  represents alkyl group, alkenyl group, aromatic hydrocarbon group, heterocyclic group, R 6 —O— or R 7 —N(R 8 )—; where R 6  represents alkyl group, alkenyl group, aromatic hydrocarbon group or heterocyclic group; R 7  and R 8  each represents hydrogen atom, alkyl group, alkenyl group, aromatic hydrocarbon group or heterocyclic group, and, R 4  and R 5  represent the same groups as R 7  and R 8 , respectively, and R 4  and R 5  optionally form a ring together; and X represents —O— or —N(R 9 )—, where R 9  represents hydrogen atom or alkyl group, and X optionally forms a ring together with R 4  or R 5 , and processes for preparing α-keto amide compound using the same.

This is a divisional application of Ser. No. 10/331,702, filed Dec. 30,2002, which is in turn a continuation-in-part application ofPCT/JP01/05668 filed on Jun. 29, 2001 claiming priorities of JapanesePatent Applications No. 2000-198089, No. 2000-198090 and No. 2000-198091all of which were filed on Jun. 30, 2000, now abandoned. The subjectmatter of the aforementioned prior applications is hereby incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to an epoxycarboxamide compound, an azidecompound, and an amino alcohol compound, and a process for preparing anα-keto amide compound using them, and more particularly to anepoxycarboxamide compound, an azide compound, and an amino alcoholcompound, which can be used as an intermediate product in thepreparation of an α-keto amide compound having a protease inhibitingactivity, and a process for preparing an α-keto amide compound using theabove compounds.

BACKGROUND ART

It is known that a protease, which is a proteolytic enzyme, isresponsible for the onset and progression of various diseases such ashypertension, thrombosis, pancreatitis, cancer, an Alzheimer disease,pulmonary emphysema, a nerve degeneration disease, an allergic disease,muscular dystrophy, a rheumatic disease, osteoporosis and a periodontaldisease (Protein, Nucleic Acid, and Enzyme, vol. 42, No. 14 (1997); andExperimental Medicine, vol. 17, No. 15 (1999)), and inhibitor substancesof protease, namely, protease inhibitors are expected as a target ofmedicines.

An α-keto amide compound, which has been reported (Japanese ProvisionalPatent Publication No. 149166/1992; Japanese Provisional PatentPublication No. 211648/1992; Japanese PCT Provisional Patent PublicationNo. 504547/1994; WO9816512; J. Med. Chem., 39, 4089 (1996); and Exp.Opin. Ther. Patents., 8, 1707 (1998)) to have an inhibiting activitywith respect to protease, especially serine protease (elastase,tryptase, trypsin, chymotrypsin, and prolyl endopeptidase) and cysteineprotease (calpain, cathepsin B, and cathepsin L), is a compound expectedto possibly have an inhibiting activity with respect to cathepsin K,which has recently been reported to be closely responsible for bonemetabolism.

As a representative synthesis method for a protease inhibitor having anα-keto amide structure, (A) J. Med. Chem., 36, 3472 (1993) is known, andfurther, as a representative synthesis method for optically activesubstances thereof, (B) J. Med. Chem., 37, 2918 (1994) is known.

By the above (A) method, an α-keto amide compound which is a desiredcompound cannot be obtained in the form of an optically activesubstance. Further, the above (B) method has the following problems: (1)an optically active amino acid as a starting material is expensive; (2)since an amino acid is used as a starting material, only a limitedsubstituent can be introduced into the oxirane ring as substituent R¹(see general formula (I)); and (3) an α-hydroxy group in the reactionprecursor cannot be stereoselectively controlled, and therefore aproduct is obtained in the form of a diastereomer mixture andsatisfactory purification for the product is difficult. Thus, the abovemethods are not satisfactory as an industrial production process.

The present inventors have conducted extensive and intensive studieswith a view toward solving the problems accompanying the prior art. As aresult, they have found raw materials (an epoxycarboxamide compound, anazide compound, and an amino alcohol compound) for preparation of anα-keto amide compound, which are advantageous not only in thatsubstituent R¹ is not restricted by the amino acid structure, but alsoin that an α-keto amide compound can be stereoselectively formed, andthus have completed the present invention.

DISCLOSURE OF THE INVENTION

Specifically, the epoxycarboxamide compound of the present invention isrepresented by the following formula (I):

wherein R¹ represents a substituted or unsubstituted, straight, branchedor cyclic alkyl group, a substituted or unsubstituted, straight,branched or cyclic alkenyl group, a substituted or unsubstitutedaromatic hydrocarbon group or a substituted or unsubstitutedheterocyclic group, where the substituent for the alkyl group, alkenylgroup, aromatic hydrocarbon group or heterocyclic group is a substitutedor unsubstituted aromatic hydrocarbon group, a substituted orunsubstituted heterocyclic group, a substituted or unsubstituted alkoxygroup, a substituted or unsubstituted alkylthio group, a substituted orunsubstituted aryloxy group or a substituted or unsubstituted arylthiogroup; and R² represents a substituted or unsubstituted, straight,branched or cyclic alkyl group, a substituted or unsubstituted,straight, branched or cyclic alkenyl group, a substituted orunsubstituted aromatic hydrocarbon group or a substituted orunsubstituted heterocyclic group, where the substituent for the alkylgroup, alkenyl group, aromatic hydrocarbon group or heterocyclic groupis a hydroxy group, an oxo group, a halogen atom, a substituted orunsubstituted, straight, branched or cyclic alkenyl group having 2 to 6carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group,a substituted or unsubstituted heterocyclic group, a nitro group, asubstituted or unsubstituted amino group, a substituted or unsubstitutedsulfonyl group, a substituted or unsubstituted alkoxy group, asubstituted or unsubstituted alkylthio group, a substituted orunsubstituted aryloxy group, a substituted or unsubstituted arylthiogroup, an acyl group, a substituted or unsubstituted alkoxycarbonylgroup, a substituted carbamoyl group, a substituted sulfonamide group, asubstituted amide group, a mercapto group, a cyano group or amethylenedioxy group.

Also, the azide compound of the present invention is represented by thefollowing formula (VI):

wherein R¹ and R² have the same meanings as defined above.

Moreover, the amino alcohol compound of the present invention isrepresented by the following formula (IX):

wherein R¹ and R² have the same meanings as defined above, R³ representsa substituted or unsubstituted, straight, branched or cyclic alkylgroup, a substituted or unsubstituted, straight, branched or cyclicalkenyl group, a substituted or unsubstituted aromatic hydrocarbongroup, a substituted or unsubstituted heterocyclic group, R⁶—O— orR⁷—N(R⁸)—, where R⁶ represents a substituted or unsubstituted, straight,branched or cyclic alkyl group, a substituted or unsubstituted,straight, branched or cyclic alkenyl group, a substituted orunsubstituted aromatic hydrocarbon group or a substituted orunsubstituted heterocyclic group, R⁷ and R⁸ may be the same or differentfrom each other, and each represents a hydrogen atom, a substituted orunsubstituted, straight, branched or cyclic alkyl group, a substitutedor unsubstituted, straight, branched or cyclic alkenyl group, asubstituted or unsubstituted aromatic hydrocarbon group or a substitutedor unsubstituted heterocyclic group, where the substituent for the alkylgroup, alkenyl group, aromatic hydrocarbon group or heterocyclic groupis a hydroxy group, an oxo group, a halogen atom, a substituted orunsubstituted, straight, branched or cyclic alkenyl group having 2 to 6carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group,a substituted or unsubstituted heterocyclic group, a nitro group, asubstituted or unsubstituted amino group, a substituted or unsubstitutedsulfonyl group, a substituted or unsubstituted alkoxy group, asubstituted or unsubstituted alkylthio group, a substituted orunsubstituted aryloxy group, a substituted or unsubstituted arylthiogroup, an acyl group, a substituted or unsubstituted alkoxycarbonylgroup, a substituted carbamoyl group, a substituted sulfonamide group, asubstituted amide group, a mercapto group, a cyano group or amethylenedioxy group; R⁴ and R⁵ represent the same groups as R⁷ and R⁸,respectively, and R⁴ and R⁵ optionally form a ring together with thecarbon atom through which R⁴ and R⁵ are bonded; and X represents —O— or—N(R⁹)— where R⁹ represents a hydrogen atom or a substituted orunsubstituted, straight, branched or cyclic alkyl group, and Xoptionally forms a ring together with R⁴ or R⁵.

Further, the present invention provides a process for preparing anα-keto amide compound represented by the following formula (X):

wherein R¹ to R⁵ and X have the same meanings as defined above,wherein the process comprises oxidizing an amino alcohol compoundrepresented by the following formula (IX):

wherein R¹ to R⁵ and X have the same meanings as defined above.

Further, the present invention provides a process for preparing anα-keto amide compound represented by the following formula (X):

wherein R¹ to R⁵ and X have the same meanings as defined above,wherein the process comprises: reducing an azide compound represented bythe following formula (VI):

wherein R¹ and R² have the same meanings as defined above, to obtain anamine compound represented by the following formula (VII):

wherein R¹ and R² have the same meanings as defined above; condensingthe obtained amine compound with a carboxylic acid compound representedby the following formula (VIII):

wherein R³ to R⁵ and X have the same meanings as defined above,to obtain an amino alcohol compound represented by the following formula(IX):

wherein R¹ to R⁵ and X have the same meanings as defined above;

and then oxidizing the obtained amino alcohol compound.

Further, the present invention provides a process for preparing anα-keto amide compound represented by the following formula (X):

wherein R¹ to R⁵ and x have the same meanings as defined above,wherein the process comprises: subjecting an epoxycarboxamide compoundrepresented by the following formula (I):

wherein R¹ and R² have the same meanings as defined above, to epoxygroup ring-opening in the presence of a ring-opening agent to obtain anazide compound represented by the following formula (VI):

wherein R¹ and R² have the same meanings as defined above; then reducingthe obtained azide compound to obtain an amine compound represented bythe following formula (VII):

wherein R¹ and R² have the same meanings as defined above; condensingthe obtained amine compound with a carboxylic acid compound representedby the following formula (VIII):

wherein R³ to R⁵ and X have the same meanings as defined above,to obtain an amino alcohol compound represented by the following formula(IX):

-   -   wherein R¹ to R⁵ and X have the same meanings as defined above;        and then oxidizing the obtained amino alcohol compound.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinbelow, the present invention will be described in more detail.

The compounds of the present invention are represented by theabove-mentioned formulae (I), (VI) and (IX). The compound of the formula(IX) has four optical isomers represented by the following formulae(IXa) to (IXd), and all of these isomers are included in the presentinvention.

wherein R¹ to R⁵ and X have the same meanings as defined above.

In each of the above-mentioned formulae (I) and (IV) to (IX), alkylgroups in the substituted or unsubstituted alkyl groups of R¹ to R⁹ maybe individually any of straight, branched or cyclic alkyl groups having1 to 12 carbon atoms, and there may be mentioned, for example, a methylgroup, an ethyl group, a n-propyl group, a 1-methylethyl group, acyclopropyl group, a n-butyl group, a t-butyl group, a 2-methylpropylgroup, a 1-methylpropyl group, a 1,1-dimethylethyl group, a cyclobutylgroup, a n-pentyl group, a 3-methylbutyl group, a cyclopentyl group, a2,2-dimethylpropyl group, a 1-methylcyclobutyl group, a cyclobutylmethylgroup, a n-hexyl group, a 4-methylpentyl group, a cyclohexyl group, a1-methylcyclopentyl group, a cyclo-pentylmethyl group, a(1-methylcyclobutyl)methyl group, a n-heptyl group, a 5-methylhexylgroup, a 4,4-dimethylpentyl group, a cycloheptyl group, acyclohexylmethyl group, a (1-methylcyclopentyl)methyl group, a n-octylgroup, a 6-methyl-heptyl group, a 5,5-dimethylhexyl group, a(1-methylcyclohexyl)methyl group, a n-nonyl group, a 7-methyloctylgroup, a 6,6-dimethylheptyl group, a n-decyl group, an 8-methylnonylgroup, a 7,7-dimethyloctyl group, a n-undecyl group, a 9-methyldecylgroup, an 8,8-dimethylnonyl group, a n-dodecyl group, a 10-methylundecylgroup and a 9,9-dimethyldecyl group.

Also, the alkenyl groups in the substituted or unsubstituted alkenylgroups of R¹ to R⁸ may be any of straight, branched or cyclic alkenylgroups having 2 to 6 carbon atoms, and there may be mentioned, forexample, a 1-methyl-1-propenyl group, a 1-methyl-2-propenyl group, a2-methyl-2-propenyl group, an ethenyl group, a 1-methylethenyl group, a1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenylgroup, a 2-pentenyl group, a 1-pentenyl group, a 1,3-butanedienyl group,a 1-hexenyl group, a 2-hexenyl group, a 1,3-pentadienyl group and a1,3-hexadienyl group. Examples of the substituents for the alkenyl groupinclude substituted or unsubstituted aromatic hydrocarbon groups andsubstituted or unsubstituted hetero-cyclic groups mentioned below.

The substituted or unsubstituted aromatic hydrocarbon groups of R¹ to R⁸are individually a monocyclic or polycyclic aromatic hydrocarbon groupwhich optionally further has at least one substituent in its ring.Examples of such unsubstituted aromatic hydrocarbon groups include aphenyl group, a 1-naphthyl group and a 2-naphthyl group.

The substituted or unsubstituted heterocyclic groups of R¹ to R⁸ areindividually a 5-membered or 6-membered ring group having at least oneheteroatom such as a nitrogen atom, a sulfur atom and an oxygen atom, asan atom constituting the ring, and may be condensed with a benzene ring,and there may be mentioned, for example, a 2-pyridyl group, a 2-furylgroup, a 2-thienyl group, a 2-indolyl group, a 2-quinolyl group, a3-isoquinolyl group, a 2-benzofuranyl group, a 2-benzothienyl group, a2-imidazolyl group, a 2-benzimidazolyl group, a 2-thiazolyl group, a2-oxazolyl group, a 2-pyrazolyl group, a 2-pyrrimidyl group, a2-pyrrimidinyl group, a 2-dioxanyl group, a 2-thiazolidinyl group, a2-imidazolidinyl group, a 2-oxo-tetrahydrofuran-3-yl group, a2-benzothiazolyl group, a 2-quinazoline group, ahexahydro-2-azepine-3-yl group, a morpholino group, a thiamorpholinogroup, a pyrrolidino group, a piperidino group, a piperazino group, aperhydro-4-azepine-1-yl group, and a perhydro-4-azaazepine-1-yl group.These heterocyclic groups may individually have at least one substituentin their heterocyclic rings, and examples of substituents include anacetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a2-methyl-2-propyloxycarbonyl group, a methylsulfonyl group, a methoxygroup and a benzoyl group.

Examples of the substituents for the above alkyl group, alkenyl group,aromatic hydrocarbon group or heterocyclic group include a hydroxygroup, an oxo group, a halogen atom, a substituted or unsubstituted,straight, branched or cyclic alkenyl group having 2 to 6 carbon atoms, asubstituted or unsubstituted aromatic hydrocarbon group, a substitutedor unsubstituted heterocyclic group, a nitro group, a substituted orunsubstituted amino group, a substituted or unsubstituted sulfonylgroup, a substituted or unsubstituted alkoxy group, a substituted orunsubstituted alkylthio group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted arylthio group, an acyl group, asubstituted or unsubstituted alkoxycarbonyl group, a substitutedcarbamoyl group, a substituted sulfonamide group, a substituted amidegroup, a mercapto group, a cyano group and a methylenedioxy group.

Here, as examples of the alkenyl groups which are mentioned above asexamples of the substituents for the alkyl groups of R¹ to R⁹ or alkenylgroups, aromatic hydrocarbon groups or heterocyclic groups of R¹ to R⁸,there can be mentioned the same groups as the above-described alkenylgroups.

Also, as examples of the substituted or unsubstituted aromatichydrocarbon groups which are substituents for the alkyl groups of R¹ toR⁹ or the alkenyl groups, aromatic hydrocarbon groups or heterocyclicgroups of R¹ to R⁸, there can be mentioned the same groups as theabove-described aromatic hydrocarbon groups.

As examples of the substituted or unsubstituted heterocyclic groupswhich are substituents for the alkyl groups of R¹ to R⁹ or the alkenylgroups, aromatic hydrocarbon groups or heterocyclic groups of R¹ to R⁸,there can be mentioned the same groups as the above-describedheterocyclic groups.

The substituted amino groups which are substituents for the alkyl groupsof R¹ to R⁹ or the alkenyl groups, aromatic hydrocarbon groups orheterocyclic groups of R¹ to R⁸ are secondary amino groups or tertiaryamino groups substituted with various substituents, and, as examples ofthese substituents, there can be mentioned the same groups as theabove-described substituted or unsubstituted alkyl groups, substitutedor unsubstituted alkenyl groups, substituted or unsubstituted aromatichydrocarbon groups and substituted or unsubstituted hetero-cyclicgroups.

Examples of the substituted sulfonyl groups which are the substituentsfor the alkyl groups of R¹ to R⁹ or the alkenyl groups, aromatichydrocarbon groups or heterocyclic groups of R¹ to R⁸ include amethylsulfonyl group, a n-butylsulfonyl group, a2,2-dimethylethylsulfonyl group, a cyclohexylsulfonyl group, aphenylsulfonyl group, a 4-methylphenylsulfonyl group, a4-fluorophenylsulfonyl group, a 4-chlorophenylsulfonyl group, a4-nitrophenylsulfonyl group, a 2-naphthylsulfonyl group, a3,4-dimethoxyphenylsulfonyl group, a 3,4-methylenedioxy-phenylsulfonylgroup, a 2-pyridylsulfonyl group, a furyl-sulfonyl group, a2-thienylsulfonyl group, a 2-quinolylsulfonyl group, a3-isoquinolylsulfonyl group, a phenylmethylsulfonyl group, a4-fluorophenylmethylsulfonyl group, a 4-chloro-phenylmethylsulfonylgroup, a 4-nitrophenylmethylsulfonyl group, a 2-naphthylmethylsulfonylgroup, a 3,4-dimethoxy-phenylmethylsulfonyl group and a3,4-methylenedioxyphenyl-methylsulfonyl group.

The alkoxy groups which are substituents for the alkyl groups of R¹ toR⁹ or the alkenyl groups, aromatic hydrocarbon groups or heterocyclicgroups of R¹ to R⁸ are alkyl-substituted oxy groups having an alkylportion comprised of the above-mentioned alkyl group having 1 to 6carbon atoms, and examples include a methoxy group, an ethoxy group, an-propoxy group, a 1-methylethyloxy group, a n-butoxy group, a2-methylpropyloxy group, a 1-methylpropyloxy group, a2-methyl-2-propyloxy group, a 2,2-dimethylethyloxy group, a n-pentyloxygroup, a 3-methylbutyloxy group, a n-hexyloxy group, a 4-methylpentyloxygroup and a cyclohexyloxy group. As examples of substituents for thesealkoxy groups, there can be mentioned the same groups as theabove-described substituents for the alkenyl groups.

The alkylthio groups which are substituents for the alkyl groups of R¹to R⁹ or the alkenyl groups, aromatic hydrocarbon groups or heterocyclicgroups of R¹ to R⁸ are alkyl-substituted thio groups having an alkylportion comprised of the above-mentioned alkyl group having 1 to 6carbon atoms, and examples include a methylthio group, an ethylthiogroup, a n-propylthio group, a 1-methylethylthio group, a n-butylthiogroup, a 2-methylpropylthio group, a 1-methylpropylthio group, a2-methyl-2-propylthio group, a 2,2-dimethylethylthio group, an-pentylthio group, a 3-methylbutylthio group, a n-hexylthio group, a4-methylpentylthio group and a cyclohexylthio group. As examples ofsubstituents for these alkylthio groups, there can be mentioned the samegroups as the above-described substituents for the alkenyl groups.

Examples of the substituted or unsubstituted aryloxy groups which aresubstituents for the alkyl groups of R¹ to R⁹ or the alkenyl groups,aromatic hydrocarbon groups or heterocyclic groups of R¹ to R⁸ include aphenyloxy group, a 4-methylphenyloxy group, a 4-fluorophenyloxy group, a4-chlorophenyloxy group, a 4-nitrophenyloxy group, a 2-naphthyl-oxygroup, a 3,4-dimethoxyphenyloxy group, a3,4-methylene-dioxyphenyloxygroup, a 2-pyridyloxy group, a 2-furyloxygroup, a 2-thienyloxy group, a 2-quinolyloxy group, a 3-isoquinolyloxygroup, a 4-nitrophenylmethyloxy group, a 2-naphthylmethyloxy group, a3,4-dimethoxyphenyloxy group and a 3,4-methylene-dioxyphenylmethyloxygroup.

Examples of the substituted or unsubstituted arylthio groups which aresubstituents for alkyl groups of R¹ to R⁹ or the alkenyl groups,aromatic hydrocarbon groups or heterocyclic groups of R¹ to R⁸ include aphenylthio group, a 4-methylphenylthio group, a 4-fluorophenylthiogroup, a 4-chlorophenylthio group, a 4-nitrophenylthio group, a2-naphthylthio group, a 3,4-dimethoxyphenylthio group, a3,4-methylenedioxyphenylthio group, a 2-pyridylthio group, a 2-furylthiogroup, a 2-thienylthio group, a 2-quinolylthio group, a3-isoquinolylthio group, a phenylmethylthio group, a4-fluorophenylmethylthio group, a 4-chlorophenylmethylthio group, a4-nitrophenyl-methylthio group, a 2-naphthylmethylthio group, a3,4-di-methoxyphenylmethylthio group and a3,4-methylenedioxy-phenylmethylthio group.

Examples of the acyl group which are substituents for the alkyl groupsof R¹ to R⁹ or the alkenyl groups, aromatic hydrocarbon groups orheterocyclic groups of R¹ to R⁸ include an acetyl group, a propanoylgroup, a butanoyl group, a pentanoyl group, a hexanoyl group, acyclohexanecarbonyl group, a benzoyl group, a piperonyloyl group, anaphthoyl group, a pivaloyl group, a phenylacetyl group, apyridinecarbonyl group and a furan-carbonyl group.

Examples of the substituted or unsubstituted alkoxy-carbonyl groupswhich are substituents for the alkyl groups of R¹ to R⁹ or the alkenylgroups, aromatic hydrocarbon groups or heterocyclic groups of R¹ to R⁸include a methoxycarbonyl group, an ethoxycarbonyl group, an-propoxycarbonyl group, a n-butyoxycarbonyl group, a2,2-dimethylethyloxycarbonyl group, a cyclohexyloxycarbonyl group and aphenylmethyloxycarbonyl group.

The substituted carbamoyl groups which are the substituents for alkylgroups of R¹ to R⁹ or the alkenyl groups, aromatic hydrocarbon groups orheterocyclic groups of R¹ to R⁸ are groups represented by R¹⁰—NHCO— inwhich a substituent is bonded to the nitrogen atom in the carbamoylgroup. As examples of the substituents R¹⁰ bonded to the nitrogen atom,there can be mentioned the above-described substituted or unsubstitutedalkyl groups, substituted or unsubstituted alkenyl groups, substitutedor unsubstituted aromatic hydrocarbon groups, substituted orunsubstituted heterocyclic groups and substituted or unsubstituted aminogroups. Specific examples of the substituted carbamoyl groups include anN-methylcarbamoyl group, an N,N-dimethylcarbamoyl group, anN-butylcarbamoyl group, an N,N-dibutylcarbamoyl group, anN-(2,2-dimethyl-ethyl)carbamoyl group, an N-cyclohexylcarbamoyl group,an N-phenylcarbamoyl group, an N-(4-methylphenyl) carbamoyl group, anN-(4-fluorophenyl)carbamoyl group, an N-(4-chloro-phenyl) carbamoylgroup, an N-(4-nitrophenyl) carbamoyl group, an N,N-diphenylcarbamoylgroup, an N-naphthylcarbamoyl group, an N-(3,4-dimethoxyphenyl)carbamoylgroup, an N-(3,4-methylenedioxyphenyl)carbamoyl group, anN-methyl-N-phenyl-carbamoyl group, an N-methyl-N-naphthylcarbamoylgroup, an N-(2-pyridyl) carbamoyl group, an N-(2-furyl) carbamoyl group,an N-(2-thienyl)carbamoyl group, an N-(2-quinolyl)carbamoyl group, anN-(3-isoquinolyl)carbamoyl group, an N-(phenyl-methyl) carbamoyl group,an N-(4-fluorophenylmethyl) carbamoyl group, anN-(4-chlorophenylmethyl)carbamoyl group, anN-(4-nitrophenylmethyl)carbamoyl group, an N-(naphthyl-methyl)carbamoylgroup, an N-(3,4-dimethoxyphenylmethyl)-carbamoyl group and anN-(3,4-methylenedioxyphenylmethyl)-carbamoyl group.

The substituted sulfonamide groups which are the substituents for thealkyl groups of R¹ to R⁹ or the alkenyl groups, aromatic hydrocarbongroups or heterocyclic groups of R¹ to R⁸ are groups represented byR¹¹—SO₂NH— in which a substituent is bonded to the sulfur atom in thesulfonamide group, and examples of the substituents R¹¹ bonded to thesulfur atom include the above-described substituted or unsubstitutedalkyl groups, substituted or unsubstituted alkenyl groups, substitutedor unsubstituted aromatic hydrocarbon groups, substituted orunsubstituted heterocyclic groups and substituted or unsubstituted aminogroups.

The substituted amide groups which are the substituents for the alkylgroups of R¹ to R⁹ or the alkenyl groups, aromatic hydrocarbon groups orheterocyclic groups of R¹ to R⁸ are groups represented by R¹²—CONH— inwhich a substituent is bonded to the carbon atom in the amide group, andexamples of the substituents R¹² bonded to the carbon atom include aphenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, theabove-described substituted or unsubstituted alkyl groups, substitutedor unsubstituted alkenyl groups, substituted or unsubstituted aromatichydrocarbon groups, substituted or unsubstituted heterocyclic groups,substituted or unsubstituted amino groups and substituted orunsubstituted alkoxy groups.

In each of the formulae (I) and (IV) to (IX) above, examples of thesubstituted aromatic hydrocarbon groups of R¹ to R⁸ include a4-methylphenyl group, a 3,4-dimethylphenyl group, a 4-methoxyphenylgroup, a 2,3-dimethoxyphenyl group, a 3,4-dimethoxyphenyl group, a3,5-dimethoxyphenyl group, a 2,3-methylenedioxyphenyl group, a3,4-methylenedioxyphenyl group, a 4-nitrophenyl group, a3,4-dinitrophenyl group, a 4-chlorophenyl group, a 3,4-dichlorophenylgroup, a 4-bromophenyl group, a 3,4-dibromophenyl group, a 4-iodophenylgroup, a 4-fluorophenyl group, a 2,3-difluorophenyl group, a3,4-difluorophenyl group, a 3,5-difluorophenyl group, a4-trifluoromethylphenyl group, a 3-phenoxyphenyl group, a4-phenoxyphenyl group, a 4-(1-naphthoxy)phenyl group and a4-acetaminophenyl group.

The ring formed from R⁴ and R⁵ together with the carbon atom throughwhich they are bonded is a saturated cyclic alkyl group having 5 to 7carbon atoms or a saturated heterocyclic group containing a heteroatomand having 3 to 6 carbon atoms. Examples of the saturated cyclic alkylgroups having 5 to 7 carbon atoms include groups derived individuallyfrom cyclopentane, cyclohexane and cycloheptane. On the other hand,examples of the saturated heterocyclic groups containing a heteroatomand having 3 to 6 carbon atoms include groups derived individually frompyrrolidine, piperidine, piperazine, morpholine, perhydroazepine,oxolane, oxane, oxepane, thiolane, thiane and thiepane, and examples ofthe heteroatoms include an oxygen atom, a sulfur atom and a nitrogenatom. The saturated heterocyclic groups containing a heteroatom andhaving 3 to 6 carbon atoms can be fused with a benzene ring. Each of thesaturated cyclic alkyl groups having 5 to 7 carbon atoms and thesaturated heterocyclic groups containing a heteroatom and having 3 to 6carbon atoms may have a substituent, and, as examples of thesubstituents, there can be mentioned the same groups as theabove-described hydroxy group, halogen atoms, substituted orunsubstituted alkyl groups, substituted or unsubstituted aromatichydrocarbon groups including a phenyl group, a methylphenyl group and anaphthyl group, substituted or unsubstituted heterocyclic groupsincluding a thienyl group, a furyl group and a pyridyl group, nitrogroup, substituted or unsubstituted amino groups, substituted orunsubstituted sulfonyl groups, substituted or unsubstituted alkoxygroups, substituted or unsubstituted alkylthio groups, substituted orunsubstituted aryloxy groups, substituted or unsubstituted arylthiogroups, acyl group, substituted or unsubstituted alkoxycarbonyl groups,substituted carbonyl groups, mercapto group and cyano group.

The ring formed from N(R⁹) and R⁴ or R⁵ together with the carbon atomthrough which they are bonded is a saturated heterocyclic groupcontaining a nitrogen atom and having 3 to 6 carbon atoms. Examples ofthe saturated heterocyclic groups containing a nitrogen atom and having3 to 6 carbon atoms include groups derived individually frompyrrolidine, piperidine, piperazine, morpholine and perhydroazepine, andthese groups can be fused with a benzene ring. These saturatedheterocyclic groups may have a substituent, and, as examples ofsubstituents, there can be mentioned the same groups as theabove-described hydroxy group, halogenatoms, substituted orunsubstituted alkyl groups, substituted or unsubstituted aromatichydrocarbon groups including a phenyl group, a methylphenyl group and anaphthyl group, substituted or unsubstituted heterocyclic groupsincluding a thienyl group, a furyl group and a pyridyl group, nitrogroup, substituted or unsubstituted amino groups, substituted orunsubstituted sulfonyl groups, substituted or unsubstituted alkoxygroups, substituted or unsubstituted alkylthio groups, substituted orunsubstituted aryloxy groups, substituted or unsubstituted arylthiogroups, acyl group, substituted or unsubstituted alkoxycarbonyl groups,substituted carbonyl groups, mercapto group and cyano group.

In each of the compounds represented, respectively, by the formulae (I)and (VI) above, it is preferred that R¹ represents a substituted orunsubstituted, straight, branched or cyclic alkyl group, and that asubstituent for the alkyl group is a substituted or unsubstitutedaromatic hydrocarbon group, a substituted or unsubstituted heterocyclicgroup, a substituted or unsubstituted alkoxy group, a substituted orunsubstituted alkylthio group, a substituted or unsubstituted aryloxygroup or a substituted or unsubstituted arylthio group; and it ispreferred that R² represents a substituted or unsubstituted, straight,branched or cyclic alkyl group, and that a substituent for the alkylgroup is a hydroxy group, an oxo group, a halogen atom, a substituted orunsubstituted, straight, branched or cyclic alkenyl group having 2 to 6carbon atoms, a substituted or unsubstituted aromatic hydrocarbon group,a substituted or unsubstituted heterocyclic group, a nitro group, asubstituted or unsubstituted amino group, a substituted or unsubstitutedsulfonyl group, a substituted or unsubstituted alkoxy group, asubstituted or unsubstituted alkylthio group, a substituted orunsubstituted aryloxy group, a substituted or unsubstituted arylthiogroup, an acyl group, a substituted or unsubstituted alkoxycarbonylgroup, a substituted carbamoyl group, a substituted sulfonamide group, asubstituted amide group, a mercapto group, a cyano group or amethylenedioxy group.

Especially, it is preferred that R² in the formula (I) is one of theabove, straight, branched or cyclic alkyl groups having 1 to 12 carbonatoms, optionally having at least one substituent selected from thegroup consisting of a hydroxy group, an oxo group, a halogen atom, asubstituted or unsubstituted, straight, branched or cyclic alkenyl grouphaving 2 to 6 carbon atoms, a substituted or unsubstituted heterocyclicgroup, a nitro group, a substituted or unsubstituted amino group, asubstituted or unsubstituted sulfonyl group, a substituted orunsubstituted alkoxy group, a substituted or unsubstituted alkylthiogroup, a substituted or unsubstituted aryloxy group, a substituted orunsubstituted arylthio group, an acyl group, a substituted orunsubstituted alkoxycarbonyl group, a substituted carbamoyl group, asubstituted sulfonamide group, a substituted amide group, a mercaptogroup and a cyano group mentioned above and R¹ in the formula (VI) isone of the above, straight, branched or cyclic alkyl groups having 1 to6 carbon atoms, optionally having at least one substituent selected fromthe group consisting of a substituted or unsubstituted aromatichydrocarbon group, a substituted or unsubstituted heterocyclic group, asubstituted or unsubstituted alkoxy group, a substituted orunsubstituted alkylthio group, a substituted or unsubstituted aryloxygroup or a substituted or unsubstituted arylthio group mentioned above.

More preferred substituents are shown below. R¹ may be an unsubstitutedalkyl group, preferably a n-butyl group. R² may be a substituted orunsubstituted cyclic alkyl group, more specifically, a substituted orunsubstituted cyclohexyl group, preferably a hydroxycyclohexyl group; anunsubstituted alkyl group, preferably a n-butyl group; a substitutedalkyl group, preferably a methoxyoxophenylpropyl group; or a substitutedphenyl group, preferably a methylenedioxyphenyl group. R³ may be a5-membered or 6-membered heterocyclic group, preferably a morpholinogroup; an unsubstituted alkyl group, preferably a methyl group; or aphenylalkoxy group, preferably a phenylmethoxy group. One of R⁴ and R⁵may be a hydrogen atom and another may be an unsubstituted alkyl group,preferably, one of R⁴ and R⁵ is a hydrogen atom and another is a t-butylgroup; or one of R⁴ and R⁵ may be a hydrogen atom and another may be aphenylalkyl group, preferably, one of R⁴ and R⁵ is a hydrogen atom andanother is a benzyl group. Alternatively, R⁴ and R⁵ may form a saturatedcyclic alkyl group having 5 to 7 carbon atoms, preferably a saturatedcyclic alkyl group having 6 carbon atoms, together with the carbon atomthrough which R⁴ and R⁵ are bonded. X may be —NH— or —O—, and, when X is—N(R⁹)—, X and R⁴ or R⁵ together form a pyrrolidino group.

More specifically, examples of the compounds (I) include(2S-trans)-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-butyl-oxiranecarboxamide,(2S-trans)-N-[(3,4-methylenedioxy)-phenyl]-3-butyloxiranecarboxamide,(2S-trans)-N-butyl-3-butyloxiranecarboxamide and(2S-trans)-N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-butyloxiranecarboxamide.

Examples of the compounds (VI) include(2S,3S)—N—[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-azido-2-hydroxyheptanamide,(2S,3S)—N-[(3,4-methylenedioxy)phenyl]-3-azido-2-hydroxyheptanamide,(2S,3S)—N-butyl-3-azido-2-hydroxy-heptanamide and(2S,3S)—N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-azido-2-hydroxyheptanamide.

Examples of the compounds (IX) includeN-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclo-hexanecarboxamide,N-[(2S,3S)-2-hydroxy-1-[N-[(3,4-methyl-enedioxy)phenyl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide,N-[(2S,3S)-2-hydroxy-1-[N-(butyl)-amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide,N-[(2S,3S)-2-hydroxy-1-[N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]-cyclohexanecarboxamide,(2S)—N-[(2S,3S)-2-hydroxy-1-[N—[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-2-(2-methylcarbonyloxy)-3-phenylpropylamide,(2S)—N—[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-4-methyl-2-[N-(phenylmethoxy-carbonyl)amino]pentanamideand(2S)—N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-(phenylmethoxycarbonyl)pyrrolidine-2-carboxamide.

An epoxycarboxamide compound represented by the above-mentioned formula(I) can be stereoselectively prepared in accordance with the followingscheme.

wherein R¹ and R² are, respectively, the same as R¹ and

R² in the above-mentioned formula (I).

Incidentally, the compound of the formula (I) has four optical isomersrepresented by the formulae (Ia) to (Id) mentioned below, and all ofthese isomers are included in the present invention.

(Step 1-1)

This is a step of oxidizing an unsaturated alcohol compound representedby the above-mentioned formula (II) to prepare an epoxy alcohol compoundrepresented by the above-mentioned formula (III).

As an oxidation reaction to be used in this step, there may bementioned, for example, a Sharpless oxidation method.

As an oxidizing agent, t-butyl hydroperoxide, cumene hydro-peroxide ortrityl hydroperoxide can be used, and, as a catalyst, titaniumtetraisopropoxide can be used. As an asymmetric agent, there may beused, for example, a tartaric acid ester which is an optically activesubstance such as diisopropyl tartrate, diethyl tartrate and dimethyltartrate. It is desired that the reaction is effected in an inertsolvent, and there may be used, for example, a halogenated hydrocarbonsuch as dichloromethane, chloroform and dichloroethane or an aromatichydrocarbon such as benzene, toluene and xylene. The amount of theoxidizing agent used is generally an equimolar amount to a 20-fold molaramount, preferably an equimolar amount to a 10-fold molar amount,relative to the mole of the compound (II). The amount of the catalystused is generally a 0.001-fold molar amount to a 10-fold molar amount,preferably a 0.05-fold molar amount to an equimolar amount, relative tothe mole of the compound (II). The amount of the asymmetric agent usedis generally an equimolar amount to a 10-fold molar amount, preferablyan equimolar amount to a 2-fold molar amount, relative to the mole ofthe catalyst. Incidentally, the reaction can be conducted in such amanner that the temperature is gradually elevated from −40° C. to roomtemperature.

In this step, according to the stereo structures of the unsaturatedalcohol compound (II) and the asymmetric agent, four types of epoxyalcohol compounds (III) shown in Table 1 below can be stereoselectivelyprepared. TABLE 1 Epoxy alcohol Alcohol compound Asymmetric agentcompound

D-(−)-tartarate

L-(+)-tartarate

D-(−)-tartarate

L-(+)-tartarate

In the table, R¹ is the same as R¹ in the above-mentioned formula (I).(Step 1-2)

This step is a step of oxidizing the epoxy alcohol compound representedby the above-mentioned formula (III) while maintaining thestereostructure to prepare an epoxycarboxylic acid compound representedby the above-mentioned formula (IV).

In this step, in the reaction of oxidizing the epoxy alcohol compoundrepresented by the above-mentioned formula (III), as an oxidizing agent,an oxidization reagent such as sodium periodate and periodic acid can beused, and, as a catalyst, ruthenium chloride can be used. As a reactionsolvent, a mixed solvent of acetonitrile/carbon tetrachloride/water isdesirably used, and the reaction temperature can be −10° C. to 30° C.

With respect to the amount of the oxidizing agent used, there is noparticular limitation, and the amount can be selected from the widerange. And it is generally an equimolar amount to a 100-fold molaramount, preferably an equimolar amount to a 10-fold molar amount,relative to the mole of the compound (III).

(Step 1-3)

This step is a step of condensing the epoxycarboxylic acid compoundrepresented by the above-mentioned formula (IV) with an amine compound(V) while maintaining the stereostructure to prepare an epoxycarboxamidecompound represented by the above-mentioned formula (I).

In this step, the epoxycarboxylic acid compound represented by theabove-mentioned formula (IV) can be condensed with an amine compoundrepresented by the above-mentioned formula (V) after converting thecarboxyl group in epoxycarboxylic acid compound (IV) to a mixed acidanhydride using pivaloyl chloride, isobutyl chlorocarbonate, ethylchlorocarbonate, p-toluene-sulfonyl chloride or methanesulfonyl chloridein the presence of a base such as triethylamine, pyridine anddimethyl-aminopyridine. It is desired that the reaction is effected inan inert solvent, and, for example, a halogenated hydrocarbon such asdichloromethane, chloroform and dichloroethane, an aromatic hydrocarbonsuch as benzene, toluene and xylene, an ether such as diethyl ether,dimethoxyethane, tetrahydrofuran and dioxane, dimethylformamide,acetonitrile, an dethylacetate can be used individually or incombination. The reaction temperature can be −20° C. to 40° C.

The reaction between the epoxycarboxylic acid compound (IV) and theamine compound (V) can be carried out in the presence of a condensingagent, and, as the condensing agent, for example, a carbodiimide reagentsuch as dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and iso-propylcarbodiimidecan be used.

Further, in this step, the epoxycarboxylic acid compound (IV) iscondensed with N-hydroxysuccinimide, p-nitrophenol or1-hydroxybenzotriazole using the above-mentioned condensing agent toform an active ester product, and then the product formed can be reactedwith the amine compound (V).

The epoxycarboxamide compound represented by the above-mentioned formula(I) is subjected to, for example, reaction in accordance with theformula mentioned below to stereoselectively form an azide compoundrepresented by the above-mentioned formula (VI).

wherein R¹ and R² are, respectively, the same as R¹ and

R² in the above-mentioned formula (I).

(Second Step)

This step is a step of subjecting the epoxycarboxamide compoundrepresented by the above-mentioned formula (I) to regioselectivering-opening to stereoselectively prepare an azide compound representedby the above-mentioned formula (VI).

As a ring-opening agent to be used in this step, sodium azide-anhydrousmagnesium sulfate can be used, and, instead of anhydrous magnesiumsulfate, ammonium chloride can be used. As a reaction solvent, there maybe used, for example, an alcohol solvent such as methanol, ethanol,propanol and 2-methoxyethanol, or acetonitrile. The reaction temperaturecan be 50° C. to 150° C.

In this step, the azide compounds (VI) shown in the following table canbe stereoselectively prepared according to the respectivestereostructures of the epoxycarboxamide compounds (I).

Incidentally, in the compound of the formula (VI), there are fouroptical isomers represented by the following formulae (VIa) to (VId),and all of these isomers are included in the present invention. TABLE 2Epoxycarboxamide compound (I) Azide compound (VIa) to (VId)

In the table, R¹ and R² are, respectively, the same as R¹ and R² in theabove-mentioned formula (I).

The azide compound represented by the above-mentioned formula (VI) issubjected to, for example, reaction in accordance with the formulamentioned below to form an amine compound represented by the followingformula (VII):

wherein R¹ and R² are, respectively, the same as R¹ and

R² in the above-mentioned formula (I).

(Third Step)

This step is a step of reducing the azide compound represented by theabove-mentioned formula (VI) while maintaining the stereostructure toprepare an amine compound represented by the above-mentioned formula(VII). The reaction in this step can be made using a general reductionreaction of an azide group to an amino group.

As a reduction reaction to be used in this step, a catalytic reductionmethod can be used, and, as a catalyst, there may be used, for example,Pd—C (palladium-carbon) or Pd black. As a reaction solvent, there may beused an alcohol solvent such as methanol and ethanol, and the reactiontemperature can be room temperature to 40° C. The reaction pressure canbe generally normal pressure to 200 atm., preferably normal pressure to100 atm. Further, in this step, reduction can be carried out usingtriphenylphosphine and water, and it is preferred to use, as a reactionsolvent, an ether solvent such as tetrahydrofuran and dioxane.

The amino alcohol compound represented by the above-mentioned formula(IX) can be prepared in accordance with the following reaction formula:

wherein R¹ to R⁵ and X are, respectively, the same as R¹

to R⁵ and X in the above-mentioned formula (IX).

(Fourth Step)

This step is a step of condensing the amine compound represented by theabove-mentioned formula (VII) with a carboxylic acid compoundrepresented by the above-mentioned formula (VIII) while maintaining thestereostructure to prepare an amino alcohol compound represented by theabove-mentioned formula (IX).

The carboxylic acid compound represented by the above-mentioned formula(VIII) in this step can be condensed with an amine compound representedby the above-mentioned formula (VII) after converting the carboxyl groupin carboxylic acid compound (VIII) to a mixed acid anhydride usingpivaloyl chloride, isobutyl chlorocarbonate, ethyl chlorocarbonate,p-toluene-sulfonyl chloride or methanesulfonyl chloride in the presenceof a base such as triethylamine, pyridine and dimethyl-aminopyridine. Itis desired that the reaction is effected in an inert solvent, and, theremay be used, for example, a halogenated hydrocarbon such asdichloromethane, chloroform and dichloroethane, an aromatic hydrocarbonsuch as benzene, toluene and xylene, an ether such as diethyl ether,dimethoxyethane, tetrahydrofuran and dioxane, dimethylformamide,acetonitrile and ethyl acetate individually or in combination. Thereaction temperature can be −20° C. to 40° C.

The reaction between the carboxylic acid compound (VIII) and the aminecompound (VII) can be carried out in the presence of a condensing agent,and, as the condensing agent, there may be used, for example, acarbodiimide reagent such as dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylamino-propyl)carbodiimide andisopropylcarbodiimide.

Moreover, in this step, the carboxylic acid compound (VIII) is condensedwith N-hydroxysuccinimide, p-nitrophenol or 1-hydroxybenzotriazole usingthe above-mentioned condensing agent to form an active ester product,and then the product formed can be reacted with the amine compound(VII).

In this step, the amino alcohol compounds (IXa) to (IXd) shown in thefollowing Table 3 having stereo structures maintained, respectively,corresponding to the stereostructures of the amine compounds (VIIa) to(VIId) can be prepared. TABLE 3 Amino alcohol compound Amine compound(VIIa to VIId) (IXa to IXd)

In the table, R¹ to R⁵ and X are, respectively, the same

as R¹ to R³ and X in the above-mentioned formula (IX).

The amino alcohol compound represented by the above-mentioned formula(IX) is subjected to, for example, reaction in accordance with thefollowing formula to form an α-keto amide compound (X) having acathepsin K inhibiting activity.

wherein R¹ to R⁵ and X are, respectively, the same as

to R⁵ and X in the above-mentioned formula (IX).

(Fifth Step)

This step is a step of oxidizing the amino alcohol compound representedby the above-mentioned formula (IX) to prepare an α-keto amide compoundrepresented by the above-mentioned formula (X).

In this step, a general oxidation reaction of a hydroxy group to aketone can be used. As an oxidation reaction to be used in this step,there may be used, for example, an active dimethyl sulfoxide oxidationmethod. As an oxidizing agent, dimethyl sulfoxide is used in combinationwith an activating agent such as dicyclohexylcarbodiimide, diphosphoruspentoxide, a pyridine-sulfur trioxide complex, oxalyl chlorode, aceticanhydride and trifluoroacetic acid. The amount of the activating agentused is an equivalent amount to a 12 equivalent amount relative to theamino alcohol compound represented by the above-mentioned formula (IX).It is preferred that the reaction is effected in a solvent, and theremay be used, for example, a halogenated hydrocarbon such asdichloromethane, chloroform and dichloroethane, or else, dimethylsulfoxide as an oxidizing agent in an excess amount can be used as asolvent. The reaction can be advanced at −78° C. to 30° C.

In this step, the α-keto amide compounds (X) shown in the followingTable 4 having stereostructures of R¹ maintained, respectively,corresponding to the stereostructures of the amino alcohol compounds(IX) can be prepared. TABLE 4 Amino alcohol compound α-Ketoainidecompound (IXa to IXd) (Xa to Xb)

In the table, R¹ to R⁵ and X are, respectively, the same as R¹ to R⁵ andX in the above-mentioned formula (IX).

EXAMPLES

In the following, the present invention will be explained in more detailby referring to Reference examples and Examples.

Reference Example 1 Synthesis of phenyl methyl1-aminocyclohexanecarboxylate p-toluenesulfonate

wherein TsOH represents p-toluenesulfonic acid.

In a flask were charged 50.8 g (355 mmol) of1-amino-cyclohexanecarboxylic acid, 81 g (426 mmol) of p-toluenesulfonicacid monohydrate, 180 ml of benzyl alcohol and 360 ml of toluene, andthe mixture was heated overnight using a Dean-Stark device attachedthereto a reflux condenser on an oil bath (160° C.). The formed waterwas removed by azeotropic distillation with toluene. After completion ofthe reaction, when the reaction mixture was poured into a large amountof ethyl acetate, crystals were precipitated. This crystal was washedagain with ethyl acetate to obtain 128 g (Yield: 89%) of the titlecompound.

¹H-NMR (CDCl₃, δ): 1.25-1.43 (2H, m), 1.43-1.58 (2H, m), 1.59-1.70 (2H,m), 1.83-1.94 (2H, m), 1.94-2.02 (2H, m), 2.83 (3H, s), 5.13 (2H, s),7.10 (2H, d, J=8 Hz), 7.24-7.31 (5H, m), 7.76 (2H, d, J=8 Hz), 8.30 (2H,brs)

IR (ν, KBr, cm⁻¹): 3468, 1746, 1608

FAB-Mass (m/z, %): 406 (M⁺+1, 2), 234 (100)

Reference Example 2 Synthesis of phenylmethyl1-[N-(morpholine-4-carbonyl)-amino]cyclohexanecarboxylate

After neutralizing 203 g (500 mmol) of phenylmethyl1-aminocyclohexanecarboxylate-p-toluenesulfonate with a 10% sodiumcarbonate solution, the mixture was extracted with chloroform and driedover anhydrous magnesium sulfate. The solid material was filtered off,and after adding 56 g (550 mmol) of triethylamine to the chloroformlayer, 75 g (500 mmol) of 4-morpholinecarbonyl chloride was addeddropwise, and the mixture was heated in an oil bath (60° C.) for 3 days.After completion of the reaction, the reaction mixture was washedsuccessively in the order of water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogen carbonate solutionand a saturated NaCl solution, and dried over anhydrous sodium sulfate.After removing the solvent under reduced pressure, the resultingcrystals were washed with ether to obtain 151 g (Yield: 87%) of thetitle compound.

¹H-NMR (CDCl₃, δ): 1.22-1.88 (6H, m), 1.85-1.92 (2H, m), 2.07-2.30 (2H,m), 3.45 (4H, t, J=5 Hz), 3.67 (4H, t, J=5 Hz), 4.53 (1H, s), 5.15 (2H,s), 7.31-7.34 (5H, m)

IR (ν, KBr, cm⁻¹): 3316, 1732, 1690

FAB-Mass (m/z, %): 347 (M⁺+1, 100), 234 (44)

Reference Example 3 Synthesis of1-[N-(morpholine-4-carbonyl)amino]cyclohexane-carboxylic acid

In methanol was suspended 151 g (452 mmol) of phenyl-methyl1-[N-(morpholine-4-carbonyl)amino]cyclohexane-carboxylate, 15 g of 5%palladium-active carbon was added to the suspension and the mixture wasstirred under hydrogen stream at room temperature overnight. Afterremoving the catalyst by filtration, the catalyst was washed three timeswith a mixed solvent of chloroform-methanol, and the organic layers werecombined and the solvent was distilled off under reduced pressure toobtain 112 g (Yield: 100%) of the title compound.

¹H-NMR (CDCl₃, δ): 1.35-1.39 (3H, m), 1.64-1.72 (3H, m), 1.91-1.97 (2H,m), 2.06-2.10 (2H, m), 3.43 (4H, t, J=5 Hz), 3.73 (4H, t, J=5 Hz), 4.50(1H, s)

IR (ν, KBr, cm⁻¹): 3824, 2568, 1970

FAB-Mass (m/z, %): 257 (M⁺+1, 8), 98 (100)

Reference Example 4 Synthesis of 2-heptyne-1-ol

Lithium (6.0 g, 0.9 mol) was added to 300 ml of a liquid ammoniasolution containing 180 mg (0.45 mmol) of iron (III) nitrate nonahydrateat −30 to −40° C. Moreover, at the same temperature, an ether solution(20 ml) containing 25.2 g (0.45 mol) of 2-propyne-1-ol was added to themixture and after stirring for 1.5 hours, 41.1 g (0.30 mol) of n-butylbromide was added to the mixture. The temperature of the reactionmixture was returned to room temperature and the mixture was stirredovernight. After completion of the reaction, a saturated aqueousammonium chloride solution was added to the mixture and the resultingmixture was extracted with ether (500 ml). The organic layer was washedwith a saturated NaCl solution, dried over anhydrous sodium sulfate, andthen, the solvent was removed off under reduced pressure. The residuewas distilled out under reduced pressure to obtain 21.0 g (Yield: 62.4%)of the title compound.

¹H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 1.36-1.54 (5H, m), 2.22 (2H,tt, J=7 Hz, 2 Hz), 4.25 (1H, dt, J=6 Hz, 2 Hz)

Reference Example 5 Synthesis of (trans)-2-heptene-1-ol

Under ice-cooling, to a toluene solution (5 ml) containing 4.0 g (35.66mmol) of 2-heptyne-1-ol was added 16 ml (53.49 mmol) of a toluenesolution containing 65% sodium bis(2-methoxy-ethoxy)aluminum hydride(Red-Al), and the temperature of the mixture was returned to roomtemperature and the mixture was stirred for 3 hours. After completion ofthe reaction, ice-water was added to the mixture and the resultingmixture was extracted with petroleum ether (50 ml). The organic layerwas washed with a saturated NaCl solution, dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas distilled out under reduced pressure to obtain 3.3 g (Yield: 80.6%)of the title compound.

¹H-NMR (CDCl₃, δ): 0.90 (3H, t, J=7 Hz), 1.27-1.41 (5H, m), 2.31 (2H,dt, J=7 Hz, 6 Hz), 4.09 (2H, dd, J=5 Hz, 5 Hz), 5.60-5.74 (2H, m)

Reference Example 6 Synthesis of (2R-trans)-3-butyloxiranemethanol

Under argon atmosphere, to anhydrous dichloromethane suspension (150 ml)containing 3.4 g of Molecular Sieves 4A were added 3.3 g (14.08 mmol) ofdiisopropyl D-(−)-tartarate, 3.3 g (11.73 mmol) of titaniumtetraisopropoxide and 13.4 g (117.30 mmol) of (trans)-2-heptene-1-ol at−30 to −40° C. and the mixture was stirred for 10 minutes. The reactionmixture was cooled to −60° C., and under stirring, 105 ml of a toluenesolution containing 2.23M of t-butylhydroperoxide was added dropwise tothe mixture over 20 minutes, and the temperature of the resultingmixture was returned to room temperature over 2 hours. After completionof the reaction, the reaction mixture was added to an aqueous solution(400 ml) containing iron (III) sulfate heptahydrate (80 g) andL-tartaric acid (40 g), and the resulting mixture was extracted withdichloromethane (400 ml). The organic layer was washed with a saturatedNaCl solution, dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure. To the residue were added ether (400 ml)and 1N-sodium hydroxide (200 ml), and the mixture was stirred at roomtemperature for one hour. After completion of the reaction, the organiclayer was separated, and the aqueous layer was extracted with ether (50ml). The organic layer was washed with a saturated NaCl solution, driedover anhydrous sodium sulfate, and the solvent was removed under reducedpressure. The residue was evaporated under reduced pressure to obtain11.6 g (Yield: 76.2%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.92 (3H, t, J=7 Hz), 1.34-1.48 (4H, m), 1.56-1.61(2H, m), 1.73 (1H, brs), 2.91-2.98 (2H, m), 3.63 (1H, ddd, J=12 Hz, 8Hz, 4 Hz), 3.92 (1H, ddd, J=12 Hz, 6 Hz, 3 Hz)

IR (ν, NaCl (film), cm¹): 3456, 2936, 2864, 1470, 1030, 880

FAB-Mass (m/z, %): 131 (M⁺+1, 58), 113 (84), 95 (100), 69 (93)

Reference Example 7 Synthesis of (2S-trans)-3-butyl-oxirane carboxylicacid-dicyclohexylammonium salt

Under ice-cooling, to a mixed solution comprising 20 ml of acetonitrile,20 ml of carbon tetrachloride and 30 ml of water containing 1.30 g (10mmol) of (2R-trans)-3-butyloxirane methanol were added 5.70 g (25 mmol)of periodic acid, and then, 41 mg of ruthenium chloride n hydrate, andthe resulting mixture was stirred at room temperature for one hour.Ethyl acetate was added to the reaction mixture, and after washing withwater and then with a saturated NaCl solution, it was dried overanhydrous magnesium sulfate. Insoluble material was filtered off, andafter adding 1.63 g (9 mmol) of dicyclohexyl amine to the filtrate, thesolvent was removed under reduced pressure. Petroleum ether was added tothe resulting residue and the mixture was stirred for 2 hours. Thecrystals were collected by filtration, and further washed with petroleumether to obtain 2.30 g (Yield: 70%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 1.10-1.30 (6H, m), 1.31-1.57(9H, m), 1.58-1.71 (3H, m), 1.74-1.82 (4H, m), 1.96-2.04 (4H, m),2.90-2.94 (1H, m), 2.97-3.06 (2H, m), 3.08 (1H, d, J=2 Hz)

IR (ν, KBr, cm⁻¹): 2932, 2856, 1604, 1400

FAB-Mass (m/z, %): 326 (M⁺+1, 7), 182 (100)

Example 1 Synthesis of(2S-trans)-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-butyloxiranecarboxamide(Compound of the formula I)

Under ice-cooling, to 20 ml of an anhydrous tetrahydrofuran solutioncontaining 2.3 g (7 mmol) of (2S-trans)-3-butyl-oxirane carboxylicacid-dicyclohexylammonium salt was added 2 ml of an anhydroustetrahydrofuran solution containing 844 mg (7 mmol) of pivaloylchloride, and the mixture was stirred at the same temperature for 15minutes. Moreover, the temperature of the reaction mixture was returnedto room temperature and the mixture was further stirred for 2 hours.After removing insoluble material in the reaction mixture by filtration,the filtrate was added to 20 ml of an anhydrous tetrahydrofuran solutioncontaining 806 mg (7 mmol) of (1S,2S)-2-aminocyclohexanol underice-cooling, and the resulting mixture was stirred at room temperaturefor 2 hours. Under reduced pressure, the reaction mixture wasconcentrated and ethyl acetate was added to the concentrate, and theresulting mixture was washed successively with a 10% aqueous potassiumhydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonatesolution, and then, a saturated NaCl solution. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure to obtain 1.69 g (Yield: 100%) of the titlecompound.

¹H-NMR (CDCl₃, δ): 0.92 (3H, t, J=7 Hz), 1.11-1.48 (8H, m), 1.52-1.62(1H, m), 1.64-1.76 (3H, m), 1.83-1.89 (1H, m), 2.03-2.10 (1H, m),2.90-2.95 (1H, m), 3.27 (1H, d, J=2 Hz), 3.30-3.38 (1H, m), 3.54-3.65(1H, m), 6.13 (1H, d, J=8 Hz)

IR (ν, KBr, cm⁻¹): 2932, 2860, 1650

FAB-Mass (m/z, %): 242 (M⁺+1, 100), 98 (95)

Example 2 Synthesis of(2S,3S)—N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-azido-2-hydroxyheptanamide(Compound of the formula VI)

30 ml of a methanol suspension containing 1.64 g (7 mmol) of(2S)-trans-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-butyloxiranecarboxamide,910 mg (14 mmol) of sodium azide and 868 mg (7.2 mmol) of anhydrousmagnesium sulfate was refluxed for 5 hours. After the temperature of thereaction mixture was returned to room temperature, the reaction mixturewas poured into 300 ml of water and the resulting mixture was stirredfor 2 hours. The resulting crystals were collected by filtration andwashed with water, and dried to obtain 1.45 g (Yield: 73%) of the titlecompound.

¹H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 1.19-1.53 (9H, m), 1.58-1.78(3H, m), 1.89-1.98 (1H, m), 2.03-2.11 (1H, m), 3.31-3.39 (1H, m), 3.52(1H, d, J=6 Hz), 3.61-3.71 (2H, m), 4.15 (1H, d, J=4 Hz), 4.29 (1H, t,J=4 Hz), 6.78 (1H, d, J=8 Hz)

IR (ν, KBr, cm⁻¹): 2936, 2864, 2096, 1636

FAB-Mass (m/z, %): 285 (M⁺+1, 100), 116 (97)

Reference Example 8 Synthesis of(2S,3S)—N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-amino-2-hydroxyheptanamide(Compound of the formula VII)

To 30 ml of a methanol solution containing 1.45 g (5 mmol) of(2S,3S)—N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-azido-2-hydroxyheptanamidewas added 150 mg of 5% palladium carbon, and the resulting mixture wasstirred under hydrogen atmosphere for 18 hours. Insoluble material wasfiltered off, and the filtrate was distilled under reduced pressure toobtain 1.18 g (Yield: 91%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.90 (3H, t, J=7 Hz), 1.18-1.43 (8H, m), 1.51-1.77(4H, m), 1.89-1.97 (1H, m), 2.02-2.09 (1H, m), 3.03-3.09 (1H, m),3.31-3.39 (1H, m), 3.61-3.69 (1H, m), 3.90 (1H, d, J=6 Hz), 7.31 (1H, d,J=8 Hz)

IR (ν, KBr, cm⁻¹): 3344, 2936, 2860, 1650

FAB-Mass (m/z, %): 259 (M⁺+1, 100), 86 (92)

Example 3 Synthesis ofN-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxy-cyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide (Compound of the formula IX)

Under ice-cooling, to 10 ml of an anhydrous tetrahydro-furan solutioncontaining 256 mg (1 mmol) of1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 202 mg(2 mmol) of triethylamine was added 1 ml of an anhydrous tetrahydrofuransolution containing 121 mg (1 mmol) of pivaloyl chloride, and theresulting mixture was stirred at the same temperature for 2 hours.Moreover, the temperature of the reaction mixture was returned to roomtemperature and the mixture was stirred for 18 hours. Insoluble materialin the reaction mixture was filtered off, and the filtrate was added to80 ml of a chloroform solution containing 258 mg (1 mmol) of(2S,3S)—N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-amino-2-hydroxyheptanamide,and the resulting mixture was stirred for 3 hours. Chloroform wasadditionally added to the reaction mixture, and the resulting mixturewas washed successively with a 10% aqueous potassium hydrogen sulfatesolution, a saturated aqueous sodium hydrogen carbonate solution andthen a saturated NaCl solution, dried over anhydrous magnesium sulfateand the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography to obtain 468 mg (Yield:94%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 1.17-1.44 (11H, m), 1.45-1.58(1H, m), 1.59-1.77 (6H, m), 1.82-1.97 (4H, m), 2.01-2.07 (2H, m),3.31-3.44 (5H, m), 3.59-3.69 (1H, m), 3.72 (4H, t, J=5 Hz), 3.76 (1H, d,J=4 Hz), 4.05-4.14 (2H, m), 4.75 (1H, s), 5.02 (1H, d, J=6 Hz), 6.56(1H, d, J=8 Hz), 7.03 (1H, d, J=8 Hz)

IR (ν, KBr, cm⁻¹): 3380, 2931, 2859, 1675, 1629

FAB-Mass (m/z, %): 497 (M⁺+1, 55), 211 (100)

Reference Example 9 Synthesis ofN—[(S)-1,2-dioxo-1-[N—[(S)-2-oxocyclohexyl]-amino]-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclo-hexanecarboxamide(Compound of the formula X)

Under nitrogen stream, at 0° C., 1.45 g (11.2 mmol) ofN,N-diisopropylethylamine was added dropwise to a mixed solution ofanhydrous dimethylsulfoxide (5 ml) and anhydrous dichloro-methane (5 ml)containing 1.78 g (11.2 mmol) of sulfur trioxide pyridine complex salt.Moreover, to the mixture was added an anhydrous dichloromethane (5 ml)solution containing 465 mg (0.94 mmol) ofN-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide,and the resulting mixture was stirred at 0° C. for 3 hours. Aftercompletion of the reaction, ice-water was added to the reaction mixture,and the resulting mixture was extracted with ethyl acetate. The organiclayer was washed successively with a 10% aqueous citric acid solution, asaturated aqueous sodium hydrogen carbonate solution and a saturatedNaCl solution, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by neutral silica gelcolumn chromatography to obtain 402 mg (Yield: 87%) of the titlecompound.

¹H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 1.23-1.46 (8H, m), 1.56-2.00(10H, m), 2.03-2.20 (3H, m), 2.36-2.70 (3H, m), 3.39 (4H, t, J=5 Hz),3.72 (4H, t, J=5 Hz), 4.36-4.47 (1H, m), 4.46 (1H, s), 5.20-5.25 (1H,m), 7.76 (1H, d, J=6 Hz), 7.93 (1H, d, J=7 Hz)

IR (ν, KBr, cm⁻¹): 3380, 2931, 2859, 1675, 1629

FAB-Mass (m/z, %): 493 (M⁺+1,25), 239 (54), 211 (100)

Example 4 Synthesis of(2S-trans)-N-[(3,4-methylenedioxy)phenyl]-3-butyloxiranecarboxamide(Compound of the formula I)

Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solutioncontaining 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxiranecarboxylicacid-dicyclohexylammonium salt was added 2 ml of ananhydroustetrahydrofuran solution containing 222 mg (1.84 mmol) ofpivaloyl chloride, and the resulting mixture was stirred at the sametemperature for 15 minutes. Moreover, the temperature of the reactionmixture was returned to room temperature, and the mixture was stirredfor 2 hours. After insoluble material in the reaction mixture wasfiltred off, the filtrate was added to 10 ml of an anhydroustetrahydrofuran solution containing 252 mg (1.84 mmol) of3,4-methylene-dioxyaniline under ice-cooling, and the resulting mixturewas stirred at room temperature for 2 hours. Under reduced pressure, thereaction mixture was concentrated, ethyl acetate was added to theconcentrate, and the resulting mixture was washed successively with a10% aqueous potassium hydrogen sulfate solution, a saturated aqueoussodium hydrogen carbonate solution and then a saturated NaCl solution.The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure to obtain 484 mg (Yield:100%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.93 (3H, t, J=7 Hz), 1.22-1.51 (4H, m) 1.58-1.80(2H, m), 3.05-3.09 (1H, m), 3.33 (1H, d, J=2 Hz), 5.95 (2H, s), 6.74(1H, d, J=8 Hz), 6.81 (1H, dd, J=8 Hz, 2 Hz), 7.25 (1H, d, J=2 Hz), 7.72(1H, s)

IR (ν, NaCl, cm⁻¹): 2932, 2872, 1674

Example 5 Synthesis of(2S,3S)—N-[(3,4-methylenedioxy)phenyl]-3-azido-2-hydroxyheptanamide(Compound of the formula VI)

30 ml of a methanol suspension containing 484 mg (1.84 mmol) of(2S-trans)-N-[(3,4-methylenedioxy)phenyl]-3-butyl-oxiranecarboxamide,239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrousmagnesium sulfate was refluxed for 5 hours. After the temperature of thereaction mixture was returned to room temperature, the reaction mixturewas concentrated under reduced pressure, ethyl acetate was added to theconcentrate, and the resulting mixture was washed successively withwater, and then, with a saturated NaCl solution. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The residue was purified by silica gel columnchromatography to obtain 395 mg (Yield: 70%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 1.30-1.41 (2H, m), 1.42-1.80(4H, m), 3.04 (1H, brs), 3.82-3.85 (1H, m), 4.40 (1H, d, J=4 Hz), 5.96(2H, s), 6.76 (1H, d, J=8 Hz), 6.86 (1H, dd, J=8 Hz, 2 Hz), 7.27 (1H, d,J=2 Hz), 8.32 (1H, s)

IR ν, NaCl, cm⁻¹): 2932, 2872, 2104, 1658

Reference Example 10 Synthesis of(2S,3S)—N-[(3,4-methylenedioxy)phenyl]-3-amino-2-hydroxyheptanamide(Compound of the formula VII)

To 30 ml of a methanol solution containing 395 mg (1.29 mmol) of(2S,3S)—N-[(3,4-methylenedioxy)phenyl]-3-azido-2-hydroxyheptanamide wasadded 40 mg of 5% palladium carbon, and the resulting mixture wasstirred under hydrogen atmosphere for 18 hours. Insoluble materials werefiltered off, and the filtrate was distilled under reduced pressure toobtain 344 mg (Yield: 95%) of the title compound.

¹H-NMR (CDCl₃, δ):0.91 (3H, t, J=7 Hz), 1.20-1.75 (6H, m), 3.10 (1H,brs), 3.92 (1H, d, J=6 Hz), 5.95 (1H, d, J=6 Hz), 5.95 (2H, s), 6.76(1H, d, J=8 Hz), 6.86 (1H, dd, J=8 Hz, 2 Hz), 7.28 (1H, d, J=2 Hz), 9.81(1H, s)

IR (ν, KBr, cm⁻¹): 3384, 2956, 2872, 1658

Example 6 Synthesis ofN-[(2S,3S)-2-hydroxy-1-[N-[(3,4-methylene-dioxy)phenyl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide(Compound of the formula

In anhydrous dichloromethane were dissolved 344 mg (1.23 mmol) of(2S,3S)—N-[(3,4-methylenedioxy)phenyl]-3-amino-2-hydroxyheptanamide, 315mg (1.23 mmol) of1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 233 mg(1.48 mmol) of 1-hydroxybenzotriazole, and then, under nitrogen stream,284 mg (1.48 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide wasadded to the above mixture at 0° C. Thereafter, the temperature of thereaction mixture was returned to room temperature, and the mixture wasstirred overnight. The reaction mixture was concentrated under reducedpressure, the residue was dissolved in 80 ml of ethyl acetate, and theresulting mixture was washed successively with water, a 10% aqueouspotassium hydrogen sulfate solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated NaCl solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to obtain 574 mg(Yield: 90%) of the desired compound.

¹H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 1.24-1.42 (6H, m), 1.52-1.72(10H, m), 1.80-2.10 (4H, m), 3.32 (4H, t, J=5 Hz), 3.67 (4H, t, J=5 Hz),4.19-4.22 (1H, m), 4.41-4.43 (1H, m), 4.64 (1H, s), 5.50 (1H, d, J=6Hz), 5.94 (2H, s), 6.70 (1H, d, J=8 Hz), 6.89 (1H, dd, J=8 Hz, 2 Hz),7.33 (1H, d, J=2 Hz), 8.69 (1H, s)

IR (ν, KBr, cm⁻¹): 3384, 2932, 2860, 1658

Reference Example 11 Synthesis ofN—[(S)-1,2-dioxo-1-[N-[(3,4-methylenedioxy)-phenyl]amino]-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]-cyclohexanecarboxamide(Compound of the formula X)

Under nitrogen stream and at 0° C., 861 mg (6.66 mmol) ofN,N-diisopropylethylamine was added dropwise to a mixed solution ofanhydrous dimethylsulfoxide (5 ml) and anhydrous dichloro-methane (5 ml)containing 1.06 g (6.66 mmol) of sulfur trioxide pyridine complex salt.Moreover, an anhydrous dichloromethane (5 ml) solution containing 574 mg(1.11 mmol) ofN-[(2S,3S)-2-hydroxy-1-[N-(3,4-methylenedioxyphenyl-1-yl)amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexane-carboxamidewas added to the above mixture, and the resulting mixture was stirred at0° C. for 3 hours. After completion of the reaction, ice-water was addedto the reaction mixture, and the resulting mixture was extracted withethyl acetate. The organic layer was washed successively with a 10%aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated NaCl solution, dried over anhydrousmagnesium sulfate, and then, concentrated under reduced pressure. Theresidue was purified by neutral silica gel column chromatography toobtain 499 mg (Yield: 87%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 1.28-1.42 (7H, m), 1.58-1.72(4H, m), 1.85-2.17 (5H, m), 3.37 (4H, t, J=5 Hz), 3.71 (4H, t, J=5 Hz),4.43 (1H, s), 5.20-5.26 (1H, m), 5.97 (2H, s), 6.77 (1H, d, J=8 Hz),6.95 (1H, dd, J=8 Hz, 2 Hz), 7.35 (1H, d, J=2 Hz), 8.06 (1H, d, J=7 Hz),8.56 (1H, s)

IR (ν, KBr, cm⁻¹): 2928, 2860, 1666

Example 7 Synthesis of (2S-trans)-N-butyl-3-butyloxiranecarboxamide(Compound of the Formula I)

Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solutioncontaining 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxiranecarboxylicacid-dicyclohexylammonium salt was added 2 ml of an anhydroustetrahydrofuran solution containing 222 mg (1.84 mmol) of pivaloylchloride, and the resulting mixture was stirred at the same temperaturefor 15 minutes. Moreover, the temperature of the reaction mixture wasreturned to room temperature, and the mixture was stirred for 2 hours.After filtering off insoluble materials in the reaction mixture, thefiltrate was added to 10 ml of an anhydrous tetrahydrofuran solutioncontaining 135 mg (1.84 mmol) of n-butylamine under ice-cooling, and theresulting mixture was stirred at room temperature for 2 hours. Underreduced pressure, the reaction mixture was concentrated and ethylacetate was added to the concentrate, and the resulting mixture waswashed successively with a 10% aqueous potassium hydrogen sulfatesolution, a saturated aqueous sodium hydrogen carbonate solution andthen a saturated NaCl solution. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure to obtain 366 mg (Yield: 100%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.93 (3H, t, J=7 Hz), 0.94 (3H, t, J=7 Hz) 1.26-1.70(10H, m), 2.89-2.93 (1H, m), 3.17-3.25 (3H, m), 6.10 (1H, s)

IR (ν, NaCl, cm⁻¹): 2932, 2872, 1662

Example 8 Synthesis of (2S,3S)—N-butyl-3-azido-2-hydroxyheptanamide(Compound of the Formula Vi)

A suspension of 30 ml of methanol containing 366 mg (1.84 mmol) of(2S-trans)-N-butyl-3-butyloxiranecarboxamide, 239 mg (3.68 mmol) ofsodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate wasrefluxed for 5 hours. After the temperature of the reaction mixture wasreturned to room temperature, the reaction mixture was concentratedunder reduced pressure, ethyl acetate was added to the concentrate, andthe resulting mixture was washed successively with water, and then asaturated NaCl solution. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue was purified by silica gel column chromatography to obtain304 mg (Yield: 68%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.93 (3H, t, J=7 Hz), 0.95 (3H, t, J=7 Hz), 1.20-1.70(10H, m), 2.86 (1H, d, J=4 Hz), 3.25-3.35 (2H, m), 3.68-3.72 (1H, m),4.21 (1H, t, J=4 Hz), 6.54 (1H, brs)

IR (ν, NaCl, cm⁻¹): 2960, 2872, 2100, 1648

Reference Example 12 Synthesis of(2S,3S)—N-butyl-3-amino-2-hydroxyheptanamide (Compound of the FormulaVII)

To 30 ml of a methanol solution containing 304 mg (1.25 mmol) of(2S,3S)—N-butyl-3-azido-2-hydroxyheptanamide was added 30 mg of 5%palladium carbon, and the resulting mixture was stirred under hydrogenatmosphere for 18 hours. Insoluble materials were filtered off, and thefiltrate was distilled under reduced pressure to obtain 254 mg (Yield:94%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 0.93 (3H, t, J=7 Hz), 1.18-1.80(10H, m), 3.01-3.50 (1H, m), 3.23-3.29 (3H, m), 3.83 (1H, d, J=5 Hz),7.45 (1H, brs)

IR (ν, KBr, cm⁻¹): 3320, 2932, 2860, 1642

Example 9 Synthesis ofN-[(2S,3S)-2-hydroxy-1-[N-(butyl)amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexane-carboxamide(Compound of the formula IX)

In anhydrous dichloromethane were dissolved 254 mg (1.21 mmol) of(2S,3S)—N-butyl-3-amino-2-hydroxyheptanamide, 310 mg (1.21 mmol) of1-[N-(morpholine-4-carbonyl)amino]cyclo-hexanecarboxylic acid and 230 mg(1.45 mmol) of 1-hydroxy-benzotriazole, subsequently, under nitrogenstream, 278 mg (1.45 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to the solutionat 0° C. Thereafter, the temperature of the reaction mixture wasreturned to room temperature and the mixture was stirred overnight. Thereaction mixture was concentrated under reduced pressure, the residuewas dissolved in 80 ml of ethyl acetate, and the resulting mixture waswashed successively with water, a 10% aqueous potassium hydrogensulfatesolution, a saturated aqueous sodium hydrogen carbonate solution and asaturated NaCl solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 489 mg (Yield: 89%) of the desiredcompound.

¹H-NMR (CDCl₃, δ): 0.87 (3H, t, J=7 Hz), 0.94 (3H, t, J=7 Hz), 1.24-1.41(8H, m), 1.45-1.78 (8H, m), 1.84-1.94 (2H, m), 1.98-2.05 (2H, m),3.18-3.30 (2H, m), 3.70 (4H, t, J=5 Hz), 3.89 (4H, t, J=5 Hz), 4.10-4.14(1H, m), 4.26 (1H, dd, J=6 Hz, 6 Hz), 4.65 (1H, s), 5.18 (1H, d, J=6Hz), 6.73 (1H, d, J=8 Hz), 6.80 (1H, brs)

IR (ν, KBr, cm⁻¹): 3368, 2932, 2860, 1650

Reference Example 13 Synthesis ofN—[(S)-1,2-dioxo-1-[N-(butyl)amino]-3-heptyl]-1-[N—[(morpholine-4-carbonyl)amino]cyclohexanecarboxamide(Compound of the Formula X)

Under nitrogen stream, 838 mg (6.48 mmol) of N,N-di-isopropylethylaminewas added dropwise at 0° C. to a mixed solution of anhydrousdimethylsulfoxide (5 ml) and anhydrous dichloro-methane (5 ml)containing 1.03 g (6.48 mmol) of sulfur trioxide pyridine complex salt.Moreover, to the above mixture was added an anhydrous dichloromethane (5ml) solution containing 489 mg (1.08 mmol) ofN-[(2S,3S)-2-hydroxy-1-[N-(butyl)-amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclo-hexanecarboxamide,and the resulting mixture was stirred at 0° C. for 3 hours. Aftercompletion of the reaction, ice-water was added to the reaction mixture,and the resulting mixture was extracted with ethyl acetate. The organiclayer was washed successively with a 10% aqueous citric acid solution, asaturated aqueous sodium hydrogen carbonate solution and a saturatedNaCl solution, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by neutral silica gelcolumn chromatography to obtain 415 mg (Yield: 85%) of the titlecompound.

¹H-NMR (CDCl₃, δ): 0.88 (3H, t, J=7 Hz), 0.93 (3H, t, J=7 Hz), 1.22-1.42(9H, m), 1.49-1.70 (6H, m), 1.85-2.00 (3H, m), 2.06-2.15 (2H, m),3.26-3.38 (2H, m), 3.38 (4H, t, J=5 Hz), 3.72 (4H, t, J=5 Hz), 4.44 (1H,s), 5.17-5.20 (1H, m), 6.86 (1H, t, J=6 Hz), 7.94 (1H, d, J=7 Hz)

IR (ν, KBr, cm⁻¹): 3344, 2932, 2860, 1658

Example 10 Synthesis of(2S-trans)-N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-butyloxiranecarboxamide(Compound of the formula I)

Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solutioncontaining 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxirane carboxylicacid-dicyclohexylammonium salt was added 2 ml of an anhydroustetrahydrofuran solution containing 222 mg (1.84 mmol) of pivaloylchloride, and the resulting mixture was stirred at the same temperaturefor 15 minutes. Moreover, the temperature of the reaction mixture wasreturned to room temperature and the mixture was stirred for 2 hours.After filtering off insoluble materials in the reaction mixture, 187 mg(1.84 mmol) of triethylamine was added to the filtrate underice-cooling, and then, 397 mg (1.84 mmol) of L-phenylalanine methylester hydrochloride was added to the mixture, and the resulting mixturewas stirred at room temperature for 2 hours. Under reduced pressure, thereaction mixture was concentrated and ethyl acetate was added to theconcentrate, and the resulting mixture was washed successively with a10% aqueous potassium hydrogen sulfate solution, a saturated aqueoussodium hydrogen carbonate solution and then a saturated NaCl solution.The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure to obtain 558 mg (Yield:100%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.91 (3H, t, J=7 Hz), 1.20-1.45 (4H, m), 1.46-1.63(2H, m), 2.58-2.61 (1H, m), 3.01 (1H, dd, J=14 Hz, 7 Hz), 3.16 (1H, d,J=2 Hz), 3.20 (1H, dd, J=14 Hz, 7 Hz), 3.74 (3H, s), 4.81-4.87 (1H, m),6.48 (1H, d, J=8 Hz), 7.05-7.10 (2H, m), 7.24-7.31 (3H, m)

IR (ν, NaCl, cm⁻¹): 2960, 2868, 1684

Example 11 Synthesis of(2S,3S)—N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-azido-2-hydroxyheptanamide(Compound of the formula VI)

A suspension of 30 ml of methanol containing 558 mg (1.84 mmol) of(2S-trans)-N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-butyloxiranecarboxamide,239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrousmagnesium sulfate was refluxed for 5 hours. After the temperature of thereaction mixture was returned to room temperature, under reducedpressure, the reaction mixture was concentrated and ethyl acetate wasadded to the concentrate, and then, the resulting mixture was washedsuccessively with water, and then a saturated NaCl solution. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography to obtain 442 mg (Yield: 69%) of the titlecompound.

¹H-NMR (CDCl₃, δ): 0.90 (3H, t, J=7 Hz), 1.21-1.62 (6H, m), 2.87 (1H, d,J=4 Hz), 3.09 (1H, dd, J=14 Hz, 7 Hz), 3.16 (1H, dd, J=14 Hz, 7 Hz),3.59-3.63 (1H, m), 3.75 (3H, s), 4.20 (1H, dd, J=4 Hz, 4 Hz), 4.88-4.93(1H, m), 7.00 (1H, d, J=8 Hz), 7.14 (2H, d, J=8 Hz), 7.25-7.33 (3H, m)

IR (ν, KBr, cm⁻¹): 2856, 2100, 1658

Reference Example 14 Synthesis of(2S,3S)—N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-amino-2-hydroxyheptanamide(Compound of the formula VII)

To 30 ml of a methanol solution containing 442 mg (1.27 mmol) of(2S,3S)—N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-azido-2-hydroxyheptanamidewas added 45 mg of 5% palladium carbon, and the mixture was stirredunder hydrogen atmosphere for 18 hours. Insoluble materials werefiltered off, and the filtrate was distilled under reduced pressure toobtain 385 mg (Yield: 94%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7 Hz), 1.18-1.70 (6H, m) 2.86-2.91(1H, m), 3.06 (1H, dd, J=14 Hz, 7 Hz), 3.18 (1H, dd, 14 Hz, 7 Hz), 3.73(3H, s), 3.76 (1H, d, J=7 Hz), 4.86-4.92 (1H, m), 7.15 (1H, d, J=7 Hz),7.21-7.31 (5H, m), 8.15 (1H, d, J=8 Hz)

IR (ν, KBr, cm⁻¹): 3364, 2956, 2860, 1652

Example 12 Synthesis ofN-[(2S,3S)-2-hydroxy-1-[N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide(Compound of the formula IX)

In anhydrous dichloromethane were dissolved 385 mg (1.19 mmol) of(2S,3S)—N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-yl]-3-amino-2-hydroxyheptanamide,305 mg (1.19 mmol) of1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 226 mg(1.43 mmol) of 1-hydroxybenzotriazole, and subsequently, 274 mg (1.43mmol) of 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide was added tothe above mixture under nitrogen stream at 0° C. Thereafter, thetemperature of the reaction mixture was returned to room temperature andthe mixture was stirred overnight. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in 80 ml of ethylacetate, and the resulting mixture was washed successively with water, a10% aqueous potassium hydrogen sulfate solution, a saturated aqueoussodium hydrogen carbonate solution and a saturated NaCl solution, driedover an hydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 587 mg (Yield: 88%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.86 (3H, t, J=7 Hz), 1.20-1.70 (12H, m), 1.80-1.90(2H, m), 1.92-2.02 (2H, m), 3.05-3.17 (2H, m), 3.36 (4H, t, J=5 Hz),3.69 (4H, t, J=5 Hz), 3.70 (3H, s), 4.09-4.14 (1H, m), 4.34 (1H, dd, J=6Hz, 6 Hz), 4.63 (1H, s), 4.80-4.86 (1H, m), 5.00 (1H, d, J=6 Hz), 6.57(1H, d, J=8 Hz), 7.14 (1H, d, J=8 Hz), 7.20-7.30 (5H, m)

IR (ν, KBr, cm⁻¹): 3392, 2932, 2860, 1658

Reference Example 15 Synthesis ofN—[(S)-1,2-dioxo-1-[N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]amino]-3-heptyl]-1-[N—[(morpholine-4-carbonyl)amino]cyclohexanecarboxamide(Compound of the formula X)

Under nitrogen stream, 814 mg (6.30 mmol) of N,N-di-isopropylethylaminewas added dropwise at 0° C. to a mixed solution of anhydrousdimethylsulfoxide (5 ml) and anhydrous dichloro-methane (5 ml)containing 1.00 g (6.30 mmol) of sulfur trioxide pyridine complex salt.Moreover, an anhydrous dichloromethane (5 ml) solution containing 587 mg(1.05 mmol) ofN-[(2S,3S)-2-hydroxy-1-[N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]-cyclohexanecarboxamidewas added to the above mixture, and the resulting mixture was stirred at0° C. for 3 hours. After completion of the reaction, ice-water was addedto the reaction mixture, and the resulting mixture was extracted withethyl acetate. The organic layer was washed successively with a 10%aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated NaCl solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by neutral silica gel column chromatography to obtain 487mg (Yield: 83%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.87 (3H, t, J=7 Hz), 1.20-1.42 (7H, m), 1.54-1.76(4H, m), 1.80-1.96 (3H, m), 2.05-2.18 (2H, m), 3.06-3.18 (2H, m), 3.36(4H, t, J=5 Hz), 3.71 (4H, t, J=5 Hz), 3.72 (3H, s), 4.46 (1H, d, J=6Hz), 4.80-4.85 (1H, m), 5.17-5.19 (1H, m), 7.09 (1H, d, J=8 Hz), 7.12(1H, dd, J=8 Hz, 2 Hz), 7.23-7.31 (4H, m), 7.96 (1H, d, J=7 Hz)

IR (ν, KBr, cm⁻¹): 2932, 2860, 1678

Example 13 Synthesis of(2S)—N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-2-acetyloxy-3-phenylpropylamide(Compound of the formula IX)

In 20 ml of dichloromethane were dissolved 1.0 g (5.5 mmol) of(S)-2-acetyloxy-3-phenylpropanoic acid, 1.4 g (5.5 mmol) of(2S,3S)—N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-amino-2-hydroxyheptanamideand 1.0 g (6.6 mmol) of 1-hydroxybenzo-triazole, and then, 1.3 g (6.6mmol) of 1-ethyl-3-(3-di-methylaminopropyl)carbodiimide was added to theabove mixture under ice-cooling and the resulting mixture was stirredfor 18 hours. The solvent was removed under reduced pressure, ethylacetate was added to the residue, and the resulting mixture was washedsuccessively with a 10% aqueous potassium hydrogen sulfate solution, asaturated aqueous sodium hydrogen carbonate solution and then asaturated NaCl solution, dried over anhydrous magnesium sulfate and thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography to obtain 2.2 g (Yield: 84%) of thetitle compound.

¹H-NMR (CDCl₃, δ): 0.84 (3H, t, J=7 Hz), 0.99-1.37 (8H, m), 1.43-1.58(2H, m), 1.68-1.74 (2H, m), 2.01-2.10 (1H, m), 2.07 (3H, s), 3.10 (1H,dd, J=14 Hz, 7 Hz), 3.17 (1H, dd, J=14 Hz, 6 Hz), 3.38 (1H, dt, J=10 Hz,4 Hz), 3.55-3.62 (1H, m), 3.97-4.03 (1H, m), 4.16 (1H, s), 4.97 (1H,brs), 5.24 (1H, dd, J=7 Hz, 6 Hz), 6.35 (1H, d, J=8 Hz), 6.93 (1H, d,J=8 Hz), 7.18-7.31 (5H, m)

IR (ν, KBr, cm⁻¹): 3314, 2935, 1671, 1636

Reference Example 16 Synthesis of(2S)—N—[(S)-1,2-dioxo-1-[N—[(S)-2-oxocyclo-hexyl]amino]-3-heptyl]-2-acetyloxy-3-phenylpropylamide(Compound of the Formula X)

Under nitrogen stream, 700 mg (5.4 mmol) of N,N-di-isopropylethylaminewas added dropwise at 0° C. to a mixed solution of anhydrousdimethylsulfoxide (20 ml) and anhydrous dichloromethane (15 ml)containing 854 mg (5.4 mmol) of sulfur trioxide pyridine complex salt.Moreover, an anhydrous dichloromethane (5 ml) solution containing 200 mg(0.45 mmol) of(2S)—N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-2-acetyloxy-3-phenyl-propylamidewas added to the above mixture, and the resulting mixture was stirred at0° C. for 3 hours. After completion of the reaction, ice-water was addedto the reaction mixture, and the resulting mixture was extracted withethyl acetate. The organic layer was washed successively with a 10%aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated NaCl solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas washed with ether to obtain 115 mg (Yield: 58%) of the titlecompound.

¹H-NMR (CDCl₃, δ): 0.85 (3H, t, J=7 Hz), 1.10-1.94 (10H, m), 2.10 (3H,s), 2.15-2.20 (1H, m), 2.43 (1H, dt, J=13 Hz, 6 Hz), 2.56-2.68 (2H, m),3.07 (1H, dd, J=14 Hz, 7 Hz), 3.32 (1H, dd, J=14 Hz, 5 Hz), 4.38-4.44(1H, m), 5.26 (1H, dt, J=8 Hz, 5 Hz), 5.39 (1H, dd, J=7 Hz, 5 Hz), 6.55(1H, d, J=8 Hz), 7.16-7.29 (5H, m), 7.75 (1H, d, J=6 Hz)

IR (ν, KBr, cm⁻¹): 3334, 2934, 2862, 1740, 1671

Example 14 Synthesis of(2S)—N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-4-methyl-2-[N-(phenylmethoxycarbonyl)amino]pentanamide (Compound of the formula IX)

Under argon gas stream, to 25 ml of an anhydrous tetrahydrofuransolution containing 761 mg (1.1 mmol) of L-N-phenylmethoxycarbonylleucine were successively added dropwise at 0° C. 0.23 ml (1.9 mmol) ofpivaloyl chloride, and then, 40 ml of an anhydroustetrahydrofuran-chloroform (5:3) suspension containing 400 mg (1.5 mmol)of(2S,3S)—N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-amino-2-hydroxyheptanamide,and the resulting mixture was stirred at the same temperature for 2hours. Moreover, the temperature of the reaction mixture was returned toroom temperature and the mixture was stirred for 10 hours. Aftercompletion of the reaction, to the reaction mixture was added 30 ml of asaturated aqueous ammonium chloride solution, and tetrahydrofuran andchloroform were removed by distillation. The residue was extracted with50 ml of 5%-methanol/chloroform three times. The organic layers werecombined, washed with 100 ml of a saturated aqueous sodium hydrogencarbonate solution and then 100 ml of a saturated NaCl solution, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was recrystallized from 35 ml of ethanol-diethylether (5:2) to obtain 210 mg (Yield: 26.8%) of the title compound.

¹H-NMR (DMSO-d₆, δ): 0.79 (3H, t, J=7 Hz), 0.85 (3H, d, J=7 Hz), 0.87(3H, d, J=7 Hz), 1.04-1.31 (9H, m), 1.34-1.50 (3H, m), 1.52-1.66 (3H,m), 1.76-1.87 (2H, m), 3.26-3.42 (2H, m), 3.84 (1H, dd, J=6 Hz, 3 Hz),4.00-4.13 (2H, m), 4.51 (1H, d, J=5 Hz), 5.02 (2H, s), 5.71 (1H, d, J=6Hz), 7.28-7.40 (6H, m), 7.43 (1H, d, J=8 Hz), 7.47 (1H, d, J=9 Hz)

IR (ν, KBr, cm⁻¹): 3322, 2937, 1660, 1531

Reference Example 17 Synthesis of(2S)—N—[(S)-1,2-dioxo-1-[N—[(S)-2-oxocyclo-hexyl]amino]-3-heptyl]-4-methyl-2-[N-(phenylmethoxycarbon-yl)amino]pentanamide(Compound of the formula X)

Under argon gas stream, to 4 ml of an anhydrousdimethylsulfoxide-dichloromethane (1:1) solution containing 567 mg (3.6mmol) of sulfur trioxide pyridine complex salt were successively addeddropwise at 0° C. 0.62 ml (3.6 mmol) of diisopropylethylamine, and then,2 ml of an anhydrous dimethylsulfoxide solution containing 150 mg (0.3mmol) of(2S)—N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-4-methyl-2-[N-(phenyl-methoxycarbonyl)amino]pentanamide, and the mixture was stirred at the same temperature for 5hours. After completion of the reaction, 25 ml of ice-water was added tothe reaction mixture, and the resulting mixture was extracted with 20 mlof ethyl acetate three times. The organic layers were combined, washedsuccessively with 50 ml of a 10%-aqueous citric acid solution, 50 ml ofa saturated aqueous sodium hydrogen carbonate solution, and then 50 mlof a saturated NaCl solution, dried over anhydrous sodium sulfate, andthen, concentrated under reduced pressure. The residue was applied toneutral silica gel column chromatography, and eluted by a hexane-ethylacetate (11:9) eluent to obtain 120 mg of the title compound, andfurther recrystallized from 5 ml of ethyl acetate-hexane (3:2) to obtain90 mg (Yield: 60.5%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.87 (3H, t, J=7 Hz), 0.94 (6H, d, J=6 Hz) 1.20-1.55(6H, m), 1.58-1.74 (4H, m), 1.74-1.87 (1H, m), 1.87-2.00 (2H, m),2.12-2.21 (1H, m), 2.40 (1H, dt, J=14 Hz, 6 Hz), 2.53-2.61 (1H, m),2.61-2.70 (1H, m), 4.16-4.25 (1H, m), 4.37-4.45 (1H, m), 5.08-5.18 (3H,m), 5.28 (1H, dt, J=8 Hz, 5 Hz), 6.54 (1H, d, J=8 Hz), 7.29-7.40 (5H,m), 7.77 (1H, d, J=6 Hz)

IR (ν, KBr, cm⁻¹): 3320, 1689, 1661, 1526

Example 15 Synthesis of(2S)—N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-(phenyl-methoxycarbonyl)pyrrolidin-2-carboxamide(Compound of the formula IX)

In 20 ml of dimethylformamide were dissolved 523 mg (2.1 mmol) ofL-N-phenylmethoxycarbonylproline, 518 mg (2.0 mmol) of(2S,3S)—N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-amino-2-hydroxyheptanamideand 338 mg (2.2 mmol) of 1-hydroxy-benzotriazole, and under ice-cooling,423 mg (2.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide wasadded to the above solution and the resulting mixture was stirred for 18hours. To the reaction mixture was added 1N hydrochloric acid, and theresulting mixture was extracted with chloroform. The organic layer waswashed with a saturated aqueous sodium hydrogen carbonate solution andthen a saturated NaCl solution, dried over anhydrous magnesium sulfate,and the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography to obtain 709 mg (Yield:72%) of the title compound.

¹H-NMR (DMSO-d₆, δ): 0.68 (1.8H, t, J=7 Hz), 0.80 (1.2H, t, J=7 Hz),0.94-1.44 (10H, m), 1.52-1.64 (2H, m), 1.74-1.94 (5H, m), 1.97-2.18 (1H,m), 3.26-3.49 (4H, m), 3.81-3.86 (1H, m), 4.00-4.09 (1H, m), 4.23 (0.4H,dd, J=8 Hz, 3 Hz), 4.30 (0.6H, dd, J=8 Hz, 3 Hz), 4.50 (1H, d, J=5 Hz),4.93-5.11 (2H, m), 5.70 (0.4H, d, J=5 Hz), 5.75 (0.6H, d, J=5 Hz),7.24-7.40 (6H, m), 7.62 (0.4H, d, J=9 Hz), 7.70 (0.6H, d, J=9 Hz)

IR (ν, KBr, cm⁻¹): 3401, 2933, 1664, 1637

Reference Example 18 Synthesis of(2S)—N—[(S)-1,2-dioxo-1-[N—[(S)-2-oxocyclo-hexyl]amino]-3-heptyl]-1-(phenylmethoxycarbonyl)pyrrolidine-2-carboxamide(Compound of the formula X)

Under argon gas stream, to 10 ml of an anhydrousdimethylsulfoxide-dichloromethane (1:1) solution containing 1.38 g (8.6mmol) of sulfur trioxide pyridine complex salt were successively addeddropwise at 0° C. 1.47 ml (8.6 mmol) of diisopropylethylamine, and then,5 ml of an anhydrous dimethyl-sulfoxide solution containing 350 mg (0.7mmol) of(2S)—N—[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-(phenylmethoxycarbonyl)pyrrolidine-2-carboxamide, and the resulting mixture was stirred at thesame temperature for 5 hours. After completion of the reaction, to thereaction mixture was added 25 ml of ice-water, and the resulting mixturewas extracted with 30 ml of ethylacetate three times. The organic layerswere combined, washed with 100 ml of a 10%-aqueous citric acid solution,100 ml of a saturated aqueous sodium hydrogen carbonate solution, andthen, 100 ml of a saturated NaCl solution, dried over anhydrous sodiumsulfate, and then, concentrated under reduced pressure. The residue waspurified by neutral silica gel column chromatography to obtain 300 mg(Yield: 86.1%) of the title compound.

¹H-NMR (DMSO-d₆, δ): 0.77 (1.8H, t, J=7 Hz), 0.86 (1.2H, t, J=7 Hz),1.12-1.58 (6H, m), 1.63-1.92 (7H, m), 1.96-2.05 (1H, m), 2.07-2.24 (2H,m), 2.27-2.34 (1H, m), 2.48-2.58 (1H, m), 3.32-3.48 (2H, m), 4.28 (0.4H,dd, J=9 Hz, 3 Hz), 4.33 (0.6H, dd, J=9 Hz, 3 Hz), 4.39-4.47 (1H, m),4.95 (1H, ddd, J=9 Hz, 7 Hz, 3 Hz), 4.99-5.11 (2H, m), 7.25-7.40 (5H,m), 8.28 (0.4H, d, J=7 Hz), 8.32 (0.6H, d, J=7 Hz), 8.53 (0.4H, d, J=8Hz), 8.55 (0.6H, d, J=8 Hz)

IR (ν, KBr, cm⁻¹): 3320, 2935, 2863, 1704, 1666

UTILIZABILITY IN INDUSTRY

According to the present invention, a novel epoxy-carboxamide compound,azide compound and aminoalcohol compound and a process for preparing anα-keto amide compound using them can be provided, and said novelcompounds can be used as manufacturing intermediates which can be led toa useful α-ketoamide compound having a protease-inhibiting activityextremely economically and stereoselectively.

1. An epoxycarboxamide compound represented by the formula (I):

wherein R¹ represents a substituted or unsubstituted, straight, branchedor cyclic alkyl group, a substituted or unsubstituted aromatichydrocarbon group or a substituted or unsubstituted heterocyclic group,where the substituent for the alkyl group, aromatic hydrocarbon group orheterocyclic group is a substituted or unsubstituted aromatichydrocarbon group, a substituted or unsubstituted heterocyclic group, asubstituted or unsubstituted alkoxy group, a substituted orunsubstituted alkylthio group, a substituted or unsubstituted aryloxygroup or a substituted or unsubstituted arylthio group; and R²represents a substituted or unsubstituted aromatic hydrocarbon group ora substituted or unsubstituted heterocyclic group, where the substituentfor the aromatic hydrocarbon group or heterocyclic group is a hydroxygroup, an oxo group, a halogen atom, a substituted or unsubstituted,straight, branched or cyclic alkenyl group having 2 to 6 carbon atoms, asubstituted or unsubstituted aromatic hydrocarbon group, a substitutedor unsubstituted heterocyclic group, a nitro group, a substituted orunsubstituted amino group, a substituted or unsubstituted sulfonylgroup, a substituted or unsubstituted alkoxy group, a substituted orunsubstituted alkylthio group, a substituted or unsubstituted aryloxygroup, a substituted or unsubstituted arylthio group, an acyl group, asubstituted or unsubstituted alkoxycarbonyl group, a substitutedcarbamoyl group, a substituted sulfonamide group, a substituted amidegroup, a mercapto group, a cyano group or a methylenedioxy group.
 2. Theepoxycarboxamide compound according to claim 1, wherein the compoundrepresented by the formula (I) is a compound represented by thefollowing formula:

wherein R¹ and R² have the same meanings as defined above.
 3. Theepoxycarboxamide compound according to claim 1, wherein the compoundrepresented by the formula (I) is a compound represented by thefollowing formula:

wherein R¹ and R² have the same meanings as defined above.
 4. Theepoxycarboxamide compound according to claim 1, wherein the compoundrepresented by the formula (I) is a compound represented by thefollowing formula:

wherein R¹ and R² have the same meanings as defined above.
 5. Theepoxycarboxamide compound according to claim 1, wherein the compoundrepresented by the formula (I) is a compound represented by thefollowing formula:

wherein R¹ and R² have the same meanings as defined above.
 6. Theepoxycarboxamide compound according to claim 1, wherein R¹ is anunsubstituted alkyl group.
 7. The epoxycarboxamide compound according toclaim 6, wherein R¹ is an n-butyl group.
 8. The epoxycarboxamidecompound according to claim 1, wherein R² is a methylenedioxyphenylgroup.